RDH12 retinopathy: clinical features, biology, genetics and future directions

Retinol dehydrogenase 12 (RDH12) is a small gene located on chromosome 14, encoding an enzyme capable of metabolizing retinoids. It is primarily located in photoreceptor inner segments and thereby is believed to have an important role in clearing excessive retinal and other toxic aldehydes produced by light exposure. Clinical features: RDH12-associated retinopathy has wide phenotypic variability; including early-onset severe retinal dystrophy/Leber Congenital Amaurosis (EOSRD/LCA; most frequent presentation), retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. It can be inherited in an autosomal recessive and dominant fashion. RDH12-EOSRD/LCA's key features are early visual impairment, petal-shaped, coloboma-like macular atrophy with variegated watercolour-like pattern, peripapillary sparing, and often dense bone spicule pigmentation. Future directions: There is currently no treatment available for RDH12-retinopathy. However, extensive preclinical investigations and an ongoing prospective natural history study are preparing the necessary foundation to design and establish forthcoming clinical trials. Herein, we will concisely review pathophysiology, molecular genetics, clinical features, and discuss therapeutic approaches

Minimum intensity projection of embossed quadrant-detection images for improved photoreceptor mosaic visualisation

Non-confocal split-detection imaging reveals the cone photoreceptor inner segment mosaic in a plethora of retinal conditions, with the potential of providing insight to ageing, disease, and response to treatment processes, in vivo, and allows the screening of candidates for cell rescue therapies. This imaging modality complements confocal reflectance adaptive optics scanning light ophthalmoscopy, which relies on the waveguiding properties of cones, as well as their orientation toward the pupil. Split-detection contrast, however, is directional, with each cone inner segment appearing as opposite dark and bright semicircles, presenting a challenge for either manual or automated cell identification. Quadrant-detection imaging, an evolution of split detection, could be used to generate images without directional dependence. Here, we demonstrate how the embossed-filtered quadrant-detection images, originally proposed by Migacz et al. for visualising hyalocytes, can also be used to generate photoreceptor mosaic images with better and non-directional contrast for improved visualisation. As a surrogate of visualisation improvement between legacy split-detection images and the images resulting from the method described herein, we provide preliminary results of simple image processing routines that may enable the automated identification of generic image features, as opposed to complex algorithms developed specifically for photoreceptor identification, in pathological retinas

Adaptive Optics Retinal Imaging in RDH12-Associated Early Onset Severe Retinal Dystrophy

PURPOSE: RDH12 is among the most common genes found in individuals with early-onset severe retinal (EOSRD). Adaptive optics scanning light ophthalmoscopy (AOSLO) enables resolution of individual rod and cone photoreceptors in the retina. This study presents the first AOSLO imaging of individuals with RDH12-associated EOSRD. METHODS: Case series of patients who attended Moorfields Eye Hospital (London, UK). Spectral-domain optical coherence tomography, near-infrared reflectance (NIR), and blue autofluorescence imaging were analyzed. En face image sequences of photoreceptors were recorded using either of two AOSLO modalities. Cross-sectional analysis was undertaken for seven patients and longitudinal analysis for one patient. RESULTS: Nine eyes from eight patients are presented in this case series. The mean age at the time of the assessment was 11.2 ± 6.5 years of age (range 7-29). A subfoveal continuous ellipsoid zone (EZ) line was present in eight eyes. Posterior pole AOSLO revealed patches of cone mosaics. Average cone densities at regions of interest 0.5° to the fovea ranged from 12,620 to 23,660 cells/mm2, whereas intercell spacing ranged from 7.0 to 9.7 µm. CONCLUSIONS: This study demonstrates that AOSLO can provide useful high-quality images in patients with EOSRD, even during childhood, with nystagmus, and early macular atrophy. Cones at the posterior pole can appear as scattered islands or, possibly later in life, as a single subfoveal conglomerate. Detailed image analysis suggests that retinal pigment epithelial stress and dysfunction may be the initial step toward degeneration, with NIR being a useful tool to assess retinal well-being in RDH12-associated EOSRD

RPGR-Related Retinopathy: Clinical Features, Molecular Genetics, and Gene Replacement Therapy

Retinitis pigmentosa GTPase regulator (RPGR) gene variants are the predominant cause of X-linked retinitis pigmentosa (XLRP) and a common cause of cone-rod dystrophy (CORD). XLRP presents as early as the first decade of life, with impaired night vision and constriction of peripheral visual field and rapid progression, eventually leading to blindness. In this review, we present RPGR gene structure and function, molecular genetics, animal models, RPGR-associated phenotypes and highlight emerging potential treatments such as gene-replacement therapy

Effects of Intraframe Distortion on Measures of Cone Mosaic Geometry from Adaptive Optics Scanning Light Ophthalmoscopy

Purpose: To characterize the effects of intraframe distortion due to involuntary eye motion on measures of cone mosaic geometry derived from adaptive optics scanning light ophthalmoscope (AOSLO) images. Methods: We acquired AOSLO image sequences from 20 subjects at 1.0, 2.0, and 5.08 temporal from fixation. An expert grader manually selected 10 minimally distorted reference frames from each 150-frame sequence for subsequent registration. Cone mosaic geometry was measured in all registered images (n ¼ 600) using multiple metrics, and the repeatability of these metrics was used to assess the impact of the distortions from each reference frame. In nine additional subjects, we compared AOSLO-derived measurements to those from adaptive optics (AO)-fundus images, which do not contain system-imposed intraframe distortions. Results: We observed substantial variation across subjects in the repeatability of density (1.2%–8.7%), inter-cell distance (0.8%–4.6%), percentage of six-sided Voronoi cells (0.8%–10.6%), and Voronoi cell area regularity (VCAR) (1.2%–13.2%). The average of all metrics extracted from AOSLO images (with the exception of VCAR) was not significantly different than those derived from AO-fundus images, though there was variability between individual images. Conclusions: Our data demonstrate that the intraframe distortion found in AOSLO images can affect the accuracy and repeatability of cone mosaic metrics. It may be possible to use multiple images from the same retinal area to approximate a ‘‘distortionless’’ image, though more work is needed to evaluate the feasibility of this approach. Translational Relevance: Even in subjects with good fixation, images from AOSLOs contain intraframe distortions due to eye motion during scanning. The existence of these artifacts emphasizes the need for caution when interpreting results derived from scanning instruments

Multimorbidity due to novel pathogenic variants in the WFS1/RP1/NOD2 genes: autosomal dominant congenital lamellar cataract, retinitis pigmentosa and Crohn’s disease in a British family

Background: A five generation family has been analysed by whole exome sequencing (WES) for genetic associations with the multimorbidities of congenital cataract (CC), retinitis pigmentosa (RP) and Crohn’s disease (CD). // Methods: WES was performed for unaffected and affected individuals within the family pedigree followed by bioinformatic analyses of these data to identify disease-causing variants with damaging pathogenicity scores. // Results: A novel pathogenic missense variant in WFS1: c.1897G>C; p.V633L, a novel pathogenic nonsense variant in RP1: c.6344T>G; p.L2115* and a predicted pathogenic missense variant in NOD2: c.2104C>T; p.R702W are reported. The three variants cosegregated with the phenotypic combinations of autosomal dominant CC, RP and CD within individual family members. // Conclusions: Here, we report multimorbidity in a family pedigree listed on a CC register, which broadens the spectrum of potential cataract associated genes to include both RP1 and NOD2

Blue cone monochromacy: causative mutations and associated phenotypes.

PurposeTo perform a phenotypic assessment of members of three British families with blue cone monochromatism (BCM), and to determine the underlying molecular genetic basis of disease.MethodsAffected members of three British families with BCM were examined clinically and underwent detailed electrophysiological and psychophysical testing. Blood samples were taken for DNA extraction. Molecular analysis involved the amplification of the coding regions of the long (L) and medium (M) wave cone opsin genes and the upstream locus control region (LCR) by polymerase chain reaction (PCR). Gene products were directly sequenced and analyzed.ResultsIn all three families, genetic analysis identified that the underlying cause of BCM involved an unequal crossover within the opsin gene array, with an inactivating mutation. Family 1 had a single 5'-L-M-3' hybrid gene, with an inactivating Cys203Arg (C203R) mutation. Family 3 had an array composed of a C203R inactivated 5'-L-M-3' hybrid gene followed by a second inactive gene. Families 1 and 3 had typical clinical, electrophysiological, and psychophysical findings consistent with stationary BCM. A novel mutation was detected in Family 2 that had a single hybrid gene lacking exon 2. This family presented clinical and psychophysical evidence of a slowly progressive phenotype.ConclusionsTwo of the BCM-causing family genotypes identified in this study comprised different hybrid genes, each of which contained the commonly described C203R inactivating mutation. The genotype in the family with evidence of a slowly progressive phenotype represents a novel BCM mutation. The deleted exon 2 in this family is not predicted to result in a shift in the reading frame, therefore we hypothesize that an abnormal opsin protein product may accumulate and lead to cone cell loss over time. This is the first report of slow progression associated with this class of mutation in the L or M opsin genes in BCM